Molecular Genetics of Age-related Macular Degeneration

Age-related macular degeneration (AMD; OMIM # 603075) is an eye disease of the elderly, signs of which appear after the age of 50. In the Western world it is a leading cause of permanent visual loss with a prevalence of 8.5% in persons under 54 years of age and of 37% in persons over 75 years of age. Early forms of AMD may be asymptomatic, but in the late forms usually a central scotoma in the visual field follows severely complicating daily tasks. Smoking, age, and genetic predisposition are known risk factors for AMD. Until recently no true susceptibility genes had been identified though the composition of drusen deposits, the hallmarks of AMD, has suggested that the complement system might play a role in the pathogenesis of AMD. When four groups reported in March 2005, that, on chromosome 1q32, a Y402H variant in the complement factor H (CFH) gene confers risk for AMD in independent Caucasian samples, a new period in the field of genetic research of AMD started. CFH is a key regulator of the complement system. Thus, it is logical to speculate, that it plays a role in the pathogenesis of AMD. We performed a case-control association study to analyse whether the CFH Y402H variant contain a risk for AMD in the Finnish population. Although the population of Finland represents a genetic isolate, the CFH Y402H polymorphism was associated with AMD also in our patient sample with similar risk allele frequencies as in the other Caucasian populations. We further evaluated the effects of this variant, but no association between lesion subtype (predominantly classic, minimally classic or occult lesion) or lesion size of neovascular AMD and the CFH Y402H variant was detected. Neither did the variant have an effect on the photodynamic therapy (PDT) outcome. The patients that respond to PDT carried the risk genotype as frequently as those who did not respond, and no difference was found in the number of PDT sessions needed in patients with or without the risk genotypes of CFH Y402H. Functional analyses, however, showed that the binding of C-reactive protein (CRP) to CFH was significantly reduced in patients with the risk genotype of Y402H. In the past two years, the LOC387715/ high-temperature requirement factor A1 (HTRA1) locus on 10q26 has also been repeatedly associated with AMD in several populations. The recent discovery of the LOC387715 protein on the mitochondrial outer membrane suggests that the LOC387715 gene, not HTRA1, is the true predisposing gene in this region, although its biological function is still unknown. In our Finnish patient material, patients with AMD carried the A69S risk genotype of LOC387715 more frequently than the controls. Also, for the first time, an interaction between the CFH Y402H and the LOC387715 A69S variants was found. The most recently detected susceptibilty gene of AMD, the complement component 3 (C3) gene, encodes the central component of the complement system, C3. In our Finnish sample, an additive gene effect for the C3 locus was detected, though weaker than the effects for the two main loci, CFH and LOC387715. Instead, the hemicentin-1 or the elongation of very long chain fatty acids-like 4 genes that have also been suggested as candidate genes for AMD did not carry a risk for AMD in the Finnish population. This was the first series of molecular genetic study of AMD in Finland. We showed that two common risk variants, CFH Y402H and LOC387715 A69S, represent a high risk of AMD also in the isolated Finnish population, and furthermore, that they had a statistical interaction. It was demonstrated that the CFH Y402H risk genotype affects the binding of CFH to CRP thus suggesting that complement indeed plays an important role in the pathogenesis of AMD.Silmänpohjan ikärappeuma on yleisin näkövammaisuutta aiheuttava sairaus länsimaissa. Suomessa sitä esiintyy noin 40%.lla yli 70-vuotiaista. Se on silmän verkkokalvon tarkan näkemisen alueen sairaus, joka voi aiheuttaa näkökentän keskeiseen osaan laajan puutosalueen, ja voi siten heikentää näkökykyä oleellisesti. Silmänpohjan ikärappeuman kiistattomia riskitekijöitä ovat ikä, perintötekijät ja tupakointi. Molekyyligeneettisten tutkimusten avulla on voitu viime vuosina osoittaa, että silmänpohjan ikärappeumalla on vahva immunologinen tausta. Kaksi ikärappeumaan liittyvistä alttiusgeeneistä komplementtifaktori H ja C3 vaikuttavat ihmisen immuunipuolustukseen. HTRA1 ja LOC387715-geenit ovat uusia geenejä, joiden toiminnasta on vielä vähän tietoa. Näistä LOC3817715 on uusi mitokondrion ulkokalvon proteiini, joka ilmentyy verkkokalvon soluissa ja vaikuttaa todennäköiseltä alttiusgeeniltä. Tässä väitöskirjatyössä on tutkittu edellä mainittuja silmän ikärappeuman alttiusgeenejä 300 suomalaisen potilaan aineistossa. Kyseisten alttiusgeenien variantit assosioituvat ikärappeumaan myös suomalaisilla potilailla ja riskialleelien frekvenssit olivat samaa tasoa kuin muissa kaukasialaisissa populaatioissa. Väitöskirjassa selvitettiin tarkemmin CFH Y402H polymorfismin merkitystä ikärappeuman synnyssä. CFH Y402H genotyypin ei todettu vaikuttavan siihen, minkälainen pitkälle edenneen ikärappeuman muoto (predominantly classic, minimally classic tai occult) potilaalla oli tai siihen, miten ikärappeumapotilas reagoi fotodynamiseen hoitoon, joka on viime vuosiin asti ollut pääasiallinen kostean ikärappeuman hoitomuoto. Väitöskirjassa osoitettiin myös, että tekijä H:n Y402H:n genotyyppi vaikutti tulehdusta ilmentävän C-reaktiivisen proteiinin sitoutumiseen. Silmän ikärappeumaa voidaan pitää oligogeenisenä tautina eli sen syntyyn vaikuttavat vain harvat suuren riskin sisältämät geenit. Niiden löytyminen auttaa osaltaan uusien hoitomuotojen kehittämisessä

Sähköinen laskujen käsittely pk-yrityksessä

Tämän opinnäytetyön tavoitteena on selvittää, millaisia vaihtoehtoja pienyrittäjillä on sähköiseen osto- ja myyntilaskutukseen siirryttäessä. Toimeksiantajana on Maanrakennus Seitsonen Oy. Työssä tarkastellaan sähköisen laskujen käsittelyn hyötyjä ja haittoja sekä selvitetään osto- ja myyntilaskujen eri kierrätysohjelmia. Työssä kerrotaan myös verkkolaskutuksesta ja siihen siirtymisestä. Työn teoriaosuuden tavoitteena on antaa selkeä kuva lukijalle sähköisestä laskujen käsittelystä ja siihen liittyvistä ohjelmista ja järjestelmistä. Työssä kerrotaan esimerkkejä pk-yrityksen laskutusohjelma vaihtoehdoista ja niiden käyttöönotosta. Empiriaosion tarkoituksena on löytää Maanrakennus Seitsonen Oy:lle sopiva laskujenkäsittelyohjelma. Tällä hetkellä yrityksen taloushallinto hoidetaan tilitoimistossa. Tutkimuksessa päädyttiin siihen, että Maanrakennus Seitsonen Oy:n ei kannata tehdä suuria investointeja laskutusohjelman hankkimiseksi, koska kyseessä on pieni yritys jossa työskentelee vain 2 työntekijää. Yrityksellä laskujen määrät ovat toistaiseksi vielä pieniä, joten paras vaihtoehto yrityksen laskujen käsittelyyn olisi jokin Internet-pohjainen laskujen käsittelyjärjestelmä.The aim of this thesis was to clarify the options for a small company in transition to electronic invoicing. The case company is Maanrakennus Seitsonen Oy. This thesis examines the benefits and risks of electronic invoicing. Different purchase invoicing and sales invoicing softwares will also be clarified. In this thesis will also be told about electronic invoice and the implementation of electronic invoice. The target of the theoretical part was to give the reader a clear picture of electronic invoicing and related programs and systems. In this thesis there are examples from different invoicing systems for a small company. The main task was to find the best invoice prosessing program for Maanrakennus Seitsonen Oy. At the moment the company`s financial administration is taken care of by an accounting company. Maanrakennus Seitsonen is a small company, that employs only two persons. That is why the company should not make big invoicing system investments. The number of invoices in the company is small for now, so the best alternative for the company’s invoicing would be some kind of invoice program based on the Internet

Osteological material from the Stone Age and Early Metal Period sites in Karelian Isthmus and Ladoga Karelia

Subfossil refuse fauna has been collected from the Stone Age and Early Metal Period sites in Ceded Karelia ever since the early 20th century. In this article all the faunal assemblages analysed up to 2004 from the area are presented. Most of the presented assemblages derive from the excavations carried out during the first decades of the 20th century, and the fact that the early excavators often concentrated on collecting the biggest and best preserved bone fragments brings bias to the data. Only four of the analyzed sites have been excavated in the 21st century, but already these show the influence of the different excavation methods used almost hundred years apart. The recently excavated assemblages are more often dominated by small bone fragments like fish bones. Seal remains dominate most of the analyzed assemblages both on the shores of the Lake Ladoga and the Gulf of Finland, and only a few sites differ from this picture

Excavations at the Juoksemajärvi Westend Stone Age dwelling site in 2002

The first dwelling depression in the Karelian Isthmus was excavated in June 2002 jointly by Finnish and Russian researchers at the Juoksemajärvi Westend (Bol'šoe Zavetnoe 4) Stone Age dwelling site, in Räisälä municipality. There are altogether eight certain and two possible dwelling depressions known at the site; however, part of the site has been destroyed by a sandpit and thus originally there might have been even more depressions at the site. Excavations showed that the site had been used in various periods during the prehistory. The earliest occupation dates back to the Mesolithic Stone Age, which is attested by the find material and one radiocarbon date. The studied dwelling depression might date to the Early Combed Ware period but also Late Neolithic dating is possible based on finds and radiocarbon dates. Other parts of the site have also been inhabited during the Typical Combed Ware period . The nature of the site points to a relative residential sedentarity in all settlement phases and the site has been possibly used year-round

Military supply, everyday demand, and reindeer : Zooarchaeology of Nazi German Second World War military presence in Finnish Lapland, Northernmost Europe

During the Second World War, in 1941-1944, Nazi German troops held the frontal responsibility of the Arctic front in Finnish Lapland. In this paper, we present the first zooarchaeological study of the wartime faunal remains from German military camps in Lapland. This illustrates the supply situation of both the German soldiers and their multinational prisoners. The official military supply was substantially supplemented with local food sources, namely, with the local semi-domesticated reindeer that dominates the bone assemblage. Bones of cattle, ovicaprines, and pig occur in lower numbers and appear to represent the German long-distance supply chain stretching from the Mediterranean to the Arctic Ocean. The remains of reindeer and wild species remind of the close interactions with locals and of the prisoners' hunting activities to supplement their meager diet. Even if the reindeer bones dominate both the soldiers' and prisoners' faunal assemblages, there are notable differences in the body parts, with bones from meatier portions always found in the soldiers' food waste. Besides highlighting a tension between the military supply and everyday demands, the faunal remains can draw attention to wider anthropological questions that reach beyond the information available in historical documents, such as adaptations into an alien northern environment. This emphasizes the importance of zooarchaeological analyses of recent past faunal materials from superficially familiar contexts.Peer reviewe

The genetic variant rs4073 A→T of the Interleukin-8 promoter region is associated with the earlier onset of exudative age-related macular degeneration

Peer reviewe

Sotilasleiri keskellä ei mitään: liikkuminen, epäjärjestys ja arkeologia toisen maailmansodan aikaisessa saksalaisessa tukikohdassa Suomen Lapissa

This article discusses military mobilities and encampment, and associated themes such as dislocation and displacement of people, through the case of a Second World War German military camp in Finnish Lapland. The article describes the camp and its archaeological research and discusses various aspects of the camp and camp life in its particular subarctic ‘wilderness’ setting, framing the discussion within the themes of mobilities and dislocations, and especially their multiple impacts on the German troops and their multinational prisoners-ofwar based in the camp. A particular emphasis is put on how mobilities and dislocation – in effect ‘being stuck’ in a northern wilderness – were intertwined and how the inhabitants of the camp coped with the situation, as well as how this is reflected in the different features of the camp itself and the archaeological material that the fieldwork produced.This article discusses military mobilities and encampment, and associated themes such as dislocation and displacement of people, through the case of a Second World War German military camp in Finnish Lapland. The article describes the camp and its archaeological research and discusses various aspects of the camp and camp life in its particular subarctic ‘wilderness’ setting, framing the discussion within the themes of mobilities and dislocations, and especially their multiple impacts on the German troops and their multinational prisoners-of-war based in the camp. A particular emphasis is put on how mobilities and dislocation – in effect ‘being stuck’ in a northern wilderness – were intertwined and how the inhabitants of the camp coped with the situation, as well as how this is reflected in the different features of the camp itself and the archaeological material that the fieldwork produced. Keywords: Conflict archaeology, Second World War, mobility, German, Prisoner of War, Lapland, FinlandPeer reviewe

Natural history and biomarkers of retinal dystrophy caused by the biallelic TULP1 variant c.148delG

Purpose To report clinical features and potential disease markers of inherited retinal dystrophy (IRD) caused by the biallelic c.148delG variant in the tubby-like protein 1 (TULP1) gene. Methods A retrospective observational study of 16 IRD patients carrying a homozygous pathogenic TULP1 c.148delG variant. Clinical data including fundus spectral-domain optical coherence tomography (SD-OCT) were assessed. A meta-analysis of visual acuity of previously reported other pathogenic TULP1 variants was performed for reference. Results The biallelic TULP1 variant c.148delG was associated with infantile and early childhood onset IRD. Retinal ophthalmoscopy was primarily normal converting to peripheral pigmentary retinopathy and maculopathy characterized by progressive extra-foveal loss of the ellipsoid zone (EZ), the outer plexiform layer (OPL), and the outer nuclear layer (ONL) bands in the SD-OCT images. The horizontal width of the foveal EZ showed significant regression with the best-corrected visual acuity (BCVA) of the eye (p < 0.0001, R-2 = 0.541, F = 26.0), the age of the patient (p < 0.0001, R-2 = 0.433, F = 16.8), and mild correlation with the foveal OPL-ONL thickness (p = 0.014, R-2 = 0.245, F = 7.2). Modelling of the BCVA data suggested a mean annual loss of logMAR 0.027. The level of visual loss was similar to that previously reported in patients carrying other truncating TULP1 variants. Conclusions This study describes the progression of TULP1 IRD suggesting a potential time window for therapeutic interventions. The width of the foveal EZ and the thickness of the foveal OPL-ONL layers could serve as biomarkers of the disease stage.Peer reviewe